The genomic DNA in our cells is continuously damaged and repaired. The damage occurs via exposure to environmental genotoxins such as the UV component of sunlight and spontaneously due to endogenous metabolites that react with DNA. The consequences of not repairing the damage are revealed by genetic diseases in which DNA repair pathways are disrupted. Repair deficiency in humans can lead to a profound increase in the risk of cancer, even in the absence of obvious exposure to environmental genotoxins. Thus prevention of cancer is dependent upon identifying the sources of endogenous DNA damage and means to avoid or attenuate it. Mouse models of these human repair deficiency syndromes offer a sensitive tool for identifying these sources. The long term objective of this research is to use mice, genetically engineered to be deficient in DNA repair to identifying dietary sources of genotoxic stress and nutritional interventions that prevent cancer. ERCC1-XPF is an endonuclease required for nucleotide excision repair (NER) of bulky lesions on one strand of DNA and the repair of bivalent DNA interstrand crosslinks (ICL). Mice hypomorphic for ERCC1-XPF have a very high incidence of solid tumors, which cannot be attributed to their defect in NER. Thus tumorigenesis in ERCC1-XPF-deficient mice can be attributed to their defect in ICL repair, and therefore the consequence of spontaneous ICL. We hypothesize that the ICL damage that promotes spontaneous tumors in this DNA repair-deficient model is caused by lipid peroxidation (LPO). Experiments proposed will test this hypothesis by challenging the ERCC1-XPF hypomorphic mice with a diet rich in polyunsaturated fatty acids, which promote endogenous LPO. The specific aim of this project is to determine if dietary polyunsaturated fatty acids (PUFA) promote cancer. Dietary PUFA assimilate into cell membranes and are particularly vulnerable to oxidation, thus increase lipid peroxidation (LPO) in vivo. LPO of membrane PUFA produces aldehydes able to crosslink DNA. We hypothesize that LPO is a source of spontaneous ICL that contribute to tumorigenesis in the repair-deficient mice. LPO will be induced in ERCC1-XPF hypomorphic mice by administering a diet rich in PUFA. A second cohort of animals will receive an isocaloric diet depleted of PUFA. We predict that animals fed the PUFA-rich diet will have an increased incidence and/or earlier onset of solid tumors. The results from these experiments will indicate if dietary fats increase the amount of endogenous DNA damage and if this damage can promote tumorigenesis. Similarly, the results will reveal if avoiding dietary PUFA reduces cancer risk. Finally, these experiments will reveal if ERCC1-XPF hypomorphic mice are a useful model for screening anti-oxidants that may reduce cancer risk. [unreadable] [unreadable] [unreadable]